The Candidate: Dr. Gronich is a fully trained nephrologist who has recently completed his fellowship at the Massachusetts General Hospital, and has received a staff appointment in the Renal Unit. He has 2-1/2 years of laboratory experience, during which time he developed his interest in the regulation of arachidonic acid metabolism in the mesangial cell. He has two original publications: 1) on the release of arachidonic acid from mesangial cells, and 2) on the identification and characterization of a hormonally regulated form of phospholipase A2 in the mesangial cell. The latter manuscript forms the basis of the current proposal. During his research fellowship, his work was supported by a National Kidney Foundation Fellowship Award, followed by an individual National Research Service Award, through which he is currently funded. The Proposal: The release of arachidonic acid is involved in a myriad of mesangial cell functions, which have a profound impact on glomerular physiology and pathophysiologic processes. Phospholipase A2 (PLA2) is the dominant enzyme controlling arachidonic acid release in these cells, and is under stringent hormonal regulation. We have identified and characterized a novel, hormonally regulated form of PLA2 in rat renal mesangial cells. We have subsequently identified several distinct regulatory mechanisms which activate this enzyme, and have purified it to near homogeneity. We are proposing to elucidate the molecular mechanisms which regulate this important enzyme. Specifically, antibodies against the enzyme will be raised, and a cDNA clone will be isolated. These reagents will enable us to examine in detail, regulatory mechanisms suggested by our Preliminary Data. In addition, a clone for the enzyme will allow us to definitively determine the enzyme's role in mesangial cell function and examine structure function relationships. The Environment: The Renal Unit at MGH is comprised of a multi-faceted group of scientists with expertise in immunology, cell and molecular biology. These resources will prove invaluable to Dr. Gronich's research in PLA2 regulation. Dr. Dennis Ausiello, the Chief of the Renal Unit and the candidate's primary sponsor, has proven skills as a scientist and educator. He is committed to Dr. Gronich's scientific development, and will provide valuable guidance in his research. He will ensure that through close collaborations with members of the Renal Unit, Dr. Gronich acquires the resources and new methodologies necessary for his studies. Dr. Gronich will continue to benefit from his close interaction with his cosponsors, Drs. Bonventre and Nemenoff, who have longstanding interests in phospholipase activation. Dr. Nemenoff's experience in protein phosphorylation and enzyme purification, and Dr. Bonventre's knowledge of mesangial cell physiology, will provide complementary support for the proposed research. Educational resources including seminars and courses which are available at Harvard University will further enhance Dr. Gronich's development into an independent investigator.